Many obese people develop non-insulin dependent diabetes mellitus (NIDDM), while others of equivalent adiposity remain normoglycemic and do not develop diabetes mellitus. Recent evidence suggests that both genetic predisposition and regional fat distribution contribute to the categories of obese persons likely to become diabetic. For example, android distribution of fat characteristic of men is a risk factor for diabetes even in men who are moderately obese. When this hormonally modulated android pattern of fat distribution if found in women, rather than gynoid distribution, they are at an increased risk for diabetes. Since both adiposity and patterns of fat distribution are partially inherited, the complex relationship between obesity per se, regional fat metabolism, genetic background and NIDDM require new models and further investigation. An exciting new rodent model of NIDDM: the WKY fafa rat has been obtained, bred and partially described. The WKY fafa male is spontaneously diabetic and the diabetes is diet modulated. Female WKY fafas become obese, but not spontaneously diabetic, and do not respond to a high sucrose diet by expression of hyperglycemia. Specific objectives of this proposal are divided into three categories. The WKY fafa will be compared to the parent obese non-diabetic Zuckerfafa rat. This unique combination of fafa genotype on two backgrounds, one strain, but not the other, expressing the associated diabetic trait in a sexually dimorphic manner, provides a novel way to dissect independent effects of obesity and hyperglycemia. Specific hypotheses concerning effects of gonadal hormones on expression of NIDDM will be tested as will hypotheses relating in vivo and in vitro insulin resistance to hyperglycemia. Experiments to examine effects of graded simple and complex carbohydrate diets on both feeding behavior and expression of NIDDM are proposed. Thus, overall objectives are directed toward a more complete understanding of mechanisms underlying development of obesity -associated NIDDM through use of a new animal model. To test the hypothesis that gonadal hormones exert early organizational influences on NIDDM, rats will be gonadectomized neonatally. To test the hypothesis that gonadal hormones are activational, rats will be gonadectomized as adults and tested for hyperglycemia, insulin resistance, adipose tissue morphology and tissue metabolism. In some cases, replacement hormone therapy effects on expression of hyperglycemia will be studied; in others, glucose tolerance, hepatic glucose production and in vivo tissue insulin sensitivity will be examined using a combined euglycemic clamp and radiotracer methodology. Pancreatic insulin production and hepatic extraction will be studied by measuring plasma insulin and C-peptide kinetics. Hepatic FFA flux will be measured and manipulated. Regional adipose tissue triglyceride synthesis, lipoprotein lipase and glycerol release and morphology will be assessed. Insulin resistance at the cellular level will be studied using insulin binding and glucose transporter studies. Diet modulation of hyperglycemia will be studied using a computerized feeding device and on-line metabolite assessment.